Project Summary Gliomas are aggressive, highly invasive, and easily become resistant to chemotherapy and radiotherapy. The mean survival duration of patients with glioblastoma multiforme (GBM), the most common form of glioma, is approximately 1 year and there is no effective therapy to date. It is the highly invasive and proliferative nature of GBM rendering the tumor relapse and incurable. The molecular changes leading to this malignant behavior are poorly understood. The goal of this proposal is to gain definitive knowledge on the causative pathways and their mechanistic integration underlying GBM growth and invasion, which is critical for developing effective therapeutic modalities for GBM patients. Previous studies have shown that increased expression of FoxM1 is one of the most frequent alterations in GBM. Our recent study has shown that the level of FoxM1 protein expression in human glioblastoma tissues is inversely correlated with patient survival. Moreover, FoxM1 appears to be essential to glioma growth. However, the underlying mechanisms for FoxM1 overexpression are unknown. Therefore, we propose to investigate the molecular mechanisms underlying the dysregulated FoxM1 expression in GBM (Aim 1). We will determine whether the aberrant Wnt/-catenin pathway activation causes FoxM1 overexpression in GBM cells. Previous studies have indicated that constitutive activation of -catenin is not due to inactivation of the tumor suppressor APC or mutations in -catenin. To investigate the causes for the activation of -catenin/TCF-mediated transcription in GBM, we will determine the role and mechanisms of nuclear FoxM1 in enhancing -catenin/TCF4/LEF-1 transcriptional activity (Aim 2). Furthermore, Stat3 pathway is a nodal hub of gliomagenesis, while the mechanisms underlying its elevated expression and activation are unknown. Our preliminary data indicated that FoxM1 overexpression causes the dysregulated Stat3 expression and activation in GBM cells, possibly through a -catenin-mediated mechanism. Therefore, we propose to determine the regulation of Stat3 by nuclear FoxM1 and its function in FoxM1-promoted tumor development (Aim 3). If the specific aims of this grant application are completed, not only we will understand new mechanisms for the signaling integration of those major pathways, but also we will learn the biological and clinical impacts of the signaling integration on glioma development and progression. In the long term, our study may lead to the validation of molecular targets that can be used in designing effective strategies to control this deadly disease in clinics. Therefore, the findings from our proposed studies will contribute to a better understanding of the molecular mechanisms of glioma development and progression and help identify potential targets for novel therapeutic strategies against malignant glioma.